Ca2+-binding protein, EF-hand superfamily [Signal transduction mechanisms];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1002306443  13 DKDGDGKVSASELRGCMAAALgeevseeeaAAILATADTDGDGLLDHHEFMRLSAAHQLQEPAEEslrcLREAFDMyAEE 92
Cdd:COG5126    15 DADGDGVLERDDFEALFRRLW---------ATLFSEADTDGDGRISREEFVAGMESLFEATVEPF----ARAAFDL-LDT 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1002306443  93 EETAVITPASLRRMLRRLGsehqrLEMEECRAMICRFDLNGDGVLSFDEFRVMM 146
Cdd:COG5126    81 DGDGKISADEFRRLLTALG-----VSEEEADELFARLDTDGDGKISFEEFVAAV 129

EF-hand motif found in phosphoinositide phospholipase C delta (PI-PLC-delta); PI-PLC-delta isozymes represent a class of metazoan PI-PLCs that are some of the most sensitive to calcium among all PLCs. Their activation is modulated by intracellular calcium ion concentration, phospholipids, polyamines, and other proteins, such as RhoAGAP. Like other PI-PLC isozymes, PI-PLC-delta isozymes contain a core set of domains, including an N-terminal pleckstrin homology (PH) domain, four atypical EF-hand motifs, a PLC catalytic core, and a single C-terminal C2 domain. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. There are three PI-PLC-delta isozymes (1, 3 and 4). PI-PLC-delta1 is relatively well characterized. It is activated by high calcium levels generated by other PI-PLC family members, and therefore functions as a calcium amplifier within the cell. Different PI-PLC-delta isozymes have different tissue distribution and different subcellular locations. PI-PLC-delta1 is mostly a cytoplasmic protein, PI-PLC-delta3 is located in the membrane, and PI-PLC-delta4 is predominantly detected in the cell nucleus. PI-PLC-delta isozymes is evolutionarily conserved even in non-mammalian species, such as yeast, slime molds and plants.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1002306443  13 DKDGDGKVSASELRGCMAAaLGEEVSEEEAAAILATADTDGDGLLDHHEFMRLsaAHQLQEPAEeslrcLREAFDMYAEE 92
Cdd:cd16202    10 DKNGDGKLSFKECKKLLKK-LNVKVDKDYAKKLFQEADTSGEDVLDEEEFVQF--YNRLTKRPE-----IEELFKKYSGD 81

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1002306443  93 EETavITPASLRRMLRrlgsEHQRLEM---EECRAMICRF----DLNGDGVLSFDEFRVMML 147
Cdd:cd16202    82 DEA--LTVEELRRFLQ----EEQKVKDvtlEWAEQLIETYepseDLKAQGLMSLDGFTLFLL 137

XopAW family type III secretion system calcium-binding effector;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1002306443  13 DKDGDGKVSASELrgcmAAALGEEVSEEEAAAI---LATADTDGDGLLDHHEF---MRLSAAHQLQEPAEESLRCLREAF 86
Cdd:NF041410   37 DSDGDGSVSQDEL----SSALSSKSDDGSLIDLselFSDLDSDGDGSLSSDELaaaAPPPPPPPDQAPSTELADDLLSAL 112

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1002306443  87 DmyaeEEETAVITPASLRRMLRRLGSEhqrlemEECRAMICRFDLNGDGVLSFDEF 142
Cdd:NF041410  113 D----TDGDGSISSDELSAGLTSAGSS------ADSSQLFSALDSDGDGSVSSDEL 158

calmodulin; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1002306443  13 DKDGDGKVSASELrGCMAAALGEEVSEEEAAAILATADTDGDGLLDHHEFMRLSAAHQLQEPAEESlrcLREAFDMYaEE 92
Cdd:PTZ00184   21 DKDGDGTITTKEL-GTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTLMARKMKDTDSEEE---IKEAFKVF-DR 95

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1002306443  93 EETAVITPASLRRMLRRLGsehQRLEMEECRAMICRFDLNGDGVLSFDEFRVMML 147
Cdd:PTZ00184   96 DGNGFISAAELRHVMTNLG---EKLTDEEVDEMIREADVDGDGQINYEEFVKMMM 147

EF-hand domain pair;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1002306443  94 ETAVITPASLRRMLRRLGSEHqrLEMEECRAMICRFDLNGDGVLSFDEFRVMMLM 148
Cdd:pfam13833   1 EKGVITREELKRALALLGLKD--LSEDEVDILFREFDTDGDGYISFDEFCVLLER 53

EF-hand, calcium binding motif; A diverse superfamily of calcium sensors and calcium signal modulators; most examples in this alignment model have 2 active canonical EF hands. Ca2+ binding induces a conformational change in the EF-hand motif, leading to the activation or inactivation of target proteins. EF-hands tend to occur in pairs or higher copy numbers.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1002306443  82 LREAFDMYaEEEETAVITPASLRRMLRRLGSEhqrLEMEECRAMICRFDLNGDGVLSFDEFRVMM 146
Cdd:cd00051     2 LREAFRLF-DKDGDGTISADELKAALKSLGEG---LSEEEIDEMIREVDKDGDGKIDFEEFLELM 62

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1002306443  82 LREAFDMYaEEEETAVITPASLRRMLRRLGsEHQRLEMEECRAMICRFDLNGDGVLSFDEFRVMML 147
Cdd:pfam13499   4 LKEAFKLL-DSDGDGYLDVEELKKLLRKLE-EGEPLSDEEVEELFKEFDLDKDGRISFEEFLELYS 67

centrin; Provisional

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1002306443  76 EESLRCLREAFDMYaEEEETAVITPASLRRMLRRLGSEHQRlemEECRAMICRFDLNGDGVLSFDEFRVMM 146
Cdd:PTZ00183   13 EDQKKEIREAFDLF-DTDGSGTIDPKELKVAMRSLGFEPKK---EEIKQMIADVDKDGSGKIDFEEFLDIM 79

EF hand; The EF-hands can be divided into two classes: signalling proteins and buffering/transport proteins. The first group is the largest and includes the most well-known members of the family such as calmodulin, troponin C and S100B. These proteins typically undergo a calcium-dependent conformational change which opens a target binding site. The latter group is represented by calbindin D9k and do not undergo calcium dependent conformational changes.

                          10        20
                  ....*....|....*....|....*.
gi 1002306443 121 ECRAMICRFDLNGDGVLSFDEFRVMM 146
Cdd:pfam00036   1 ELKEIFRLFDKDGDGKIDFEEFKELL 26

Calcium-activated neutral; CAPN3, also termed calcium-activated neutral proteinase 3 (CANP 3), or calpain L3, or calpain p94, or muscle-specific calcium-activated neutral protease 3, or new calpain 1 (nCL-1), is a calpain large subunit that is mainly expressed in skeletal muscle, or lens. The skeletal muscle-specific CAPN3 are pathologically associated with limb girdle muscular dystrophy type 2A (LGMD2A). Its autolytic activity can be positively regulated by calmodulin (CaM), a known transducer of the calcium signal. CAPN3 is also involved in human melanoma tumorigenesis and progression. It impairs cell proliferation and stimulates oxidative stress-mediated cell death in melanoma cells. Moreover, it plays an important role in sarcomere remodeling and mitochondrial protein turnover. Furthermore, the phosphorylated skeletal muscle-specific CAPN3 acts as a myofibril structural component and may participate in myofibril-based signaling pathways. In the eye, the lens-specific CAPN3, together with CAPN2, is responsible for proteolytic cleavages of alpha and beta-crystallin. Overactivated alpha and beta-crystallin can lead to cataract formation. CAPN3 exists as a homodimer, rather than a heterodimer with the calpain small subunit. It may also form heterodimers with other calpain large subunits. CAPN3 contains a long N-terminal region, followed by a calpain cysteine protease (CysPc) domain, a C2-domain-like (C2L) domain, and a C-terminal Ca2+-binding penta-EF-hand (PEF) domain. Ca2+ binding at EF5 of the CAPN3 PEF domain is a distinct feature not observed in other calpain isoforms.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1002306443  98 ITPASLRRMLRRLGSEHQRL-----EMEECRAMICRFDLNGDGVLSFDEFR 143
Cdd:cd16190    16 ISADELRSVLNRVVKKHKDLktegfTLESCRSMIALMDTDGSGKLNLQEFR 66

Penta-EF hand, calcium binding motifs, found in PEF calpain family; The PEF calpain family belongs to the second group of penta-EF hand (PEF) proteins. It includes classical (also called conventional or typical) calpain (referring to a calcium-dependent papain-like enzymes, EC 3.4.22.17) large catalytic subunits (CAPN1, 2, 3, 8, 9, 11, 12, 13, 14) and two calpain small subunits (CAPNS1 and CAPNS2), which are largely confined to animals (metazoans). These PEF-containing are nonlysosomal intracellular calcium-activated intracellular cysteine proteases that play important roles in the degradation or functional modulation in a variety of substrates in response to calcium signalling. The classical mu- and m-calpains are heterodimers consisting of homologous but a distinct (large) L-subunit/chain (CAPN1 or CAPN2) and a common (small) S-subunit/chain (CAPNS1 or CAPNS2). These L-subunits (CAPN1 and CAPN2) and S-subunit CAPNS1 are ubiquitously found in all tissues. Other calpains likely consist of an isolated L-subunit/chain alone. Many of them, such as CAPNS2, CAPN3 (in skeletal muscle, or lens), CAPN8 (in stomach), CAPN9 (in digestive tracts), CAPN11 (in testis), CAPN12 (in follicles), are tissue-specific and have specific functions in distinct organs. The L-subunits of similar structure (called CALPA and B) also have been found in Drosophila melanogaster. The S-subunit seems to have a chaperone-like function for proper folding of the L-subunit. The catalytic L-subunits contain a short N-terminal anchor helix, followed by a calpain cysteine protease (CysPc) domain, a C2-domain-like (C2L) domain, and a C-terminal Ca2+-binding penta-EF-hand (PEF) domain. The S-subunits only have the PEF domain following an N-terminal Gly-rich hydrophobic domain. The calpains undergo a rearrangement of the protein backbone upon Ca2+-binding.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1002306443  15 DGDGKVSASELRGCMAAALGEEVSEEEAAAI------LATADTDGDGLLDHHEFMRLSAahqlqepaeeSLRCLREAFDM 88
Cdd:cd16182    11 GEDEEIDAVELQKLLNASLLKDMPKFDGFSLetcrslIALMDTNGSGRLDLEEFKTLWS----------DLKKWQAIFKK 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1002306443  89 YaEEEETAVITPASLRRMLRRLGSEHQRLEMEecrAMICRFDlNGDGVLSFDEF 142
Cdd:cd16182    81 F-DTDRSGTLSSYELRKALESAGFHLSNKVLQ---ALVLRYA-DSTGRITFEDF 129

EF-hand, calcium binding motif, found in CREC-EF hand family; The CREC (Cab45/reticulocalbin/ERC45/calumenin)-EF hand family contains a group of six EF-hand, low-affinity Ca2+-binding proteins, including reticulocalbin (RCN-1), ER Ca2+-binding protein of 55 kDa (ERC-55, also known as TCBP-49 or E6BP), reticulocalbin-3 (RCN-3), Ca2+-binding protein of 45 kDa (Cab45 and its splice variant Cab45b), and calumenin ( also known as crocalbin or CBP-50). The proteins are not only localized in various parts of the secretory pathway, but also found in the cytosolic compartment and at the cell surface. They interact with different ligands or proteins and have been implicated in the secretory process, chaperone activity, signal transduction as well as in a large variety of disease processes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1002306443  45 ILATADTDGDGLLDHHEFMRLSAAHQLQEPAEESLRCLREAFDMYAEEEETAVITPASLRRMLRRLGSEHQrleMEECRA 124
Cdd:cd15899   165 TLEDLDKNGDGFISLEEFISDPYSADENEEEPEWVKVEKERFVELRDKDKDGKLDGEELLSWVDPSNQEIA---LEEAKH 241

                          90
                  ....*....|....*..
gi 1002306443 125 MICRFDLNGDGVLSFDE 141
Cdd:cd15899   242 LIAESDENKDGKLSPEE 258

Eps15 homology domain; Pair of EF hand motifs that recognise proteins containing Asn-Pro-Phe (NPF) sequences.

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1002306443   13 DKDGDGKVSASELRGCM------AAALGEevseeeaaaILATADTDGDGLLDHHEF---MRLSAAHQLQEPAEESL 79
Cdd:smart00027  20 DKNQDGTVTGAQAKPILlksglpQTLLAK---------IWNLADIDNDGELDKDEFalaMHLIYRKLNGYPIPASL 86